Diabetes results from a reduction in endogenous functional pancreatic ?cell mass. Therefore, a priority in the field is to identify agents that enhance functional ?cell growth, regeneration, and survival, under conditions of increased ?cell stress and demand in vivo. We have recently discovered osteoprotegerin (OPG) to be a novel downstream target of lactogens in the ?cell. Preliminary studies indicate that OPG can induce endogenous rodent ?cell replication in vivo, human ?cell proliferation in vitro, delay onset of Type 1 diabetes in mice, and improve human ?cell survival against glucolipotoxicityand cytokineinduced cell death. OPG is a soluble decoy receptor. It acts by binding to its endogenous targets receptor activator of nuclear factor kappaB (RANK) ligand (RANKL) or tumor necrosis factor related apoptosisinducing ligand (TRAIL), and inhibiting their interaction with the respective receptors, RANK and death receptor. In ?cells, we found OPG induces human ?cell proliferation through inhibition of the RANKL/RANK interaction. We further confirmed the importance of this pathway using Denosumab, an FDAapproved drug for osteoporosis, and a monoclonal antibody that specifically inhibits only the RANKL/RANK pathway. Denosumab also enhances human ?cell proliferation and survival. Based on the cumulative evidence we hypothesize that OPG and Denosumab through inhibition of the RANKL/RANK pathway will have a significant therapeutic, physiologic, and mechanistic impact on the ?cell, under conditions of increased stress/demand. We will test our hypothesis through the following Specific Aims: SA 1: To assess the in vivotherapeutic potential of OPG on rodent and human ?cells under pathophysiologic conditions of increased stress and demand. SA 2: To establish the physiologic role of the RANKL/RANK pathwayin ?cells. SA 3: To understand the regulation and the intracellular mechanism of action of OPG and its partners in rodent and human ?cells. The clinical impact of the findings come from testing the effects of this pathway in vivo, in models of increased metabolic demand on rodent and human ?cells, identifying downstream targets for future drug development, and the potential for repurposing an osteoporosis drug, Denosumab, for the treatment of diabetes. The studies proposed in this application are novel, timely, and promising, with a high potential for success, based on the persuasive preliminary data. Thus, positive outcomes from these studies could have significant translationalpotential.